EP1272495B1 - A process for the preparation of highly crystalline sodium cefoperazone - Google Patents

A process for the preparation of highly crystalline sodium cefoperazone Download PDF

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Publication number
EP1272495B1
EP1272495B1 EP01940312A EP01940312A EP1272495B1 EP 1272495 B1 EP1272495 B1 EP 1272495B1 EP 01940312 A EP01940312 A EP 01940312A EP 01940312 A EP01940312 A EP 01940312A EP 1272495 B1 EP1272495 B1 EP 1272495B1
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Prior art keywords
acetone
cefoperazone
water
sodium
sodium cefoperazone
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EP01940312A
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German (de)
French (fr)
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EP1272495A2 (en
Inventor
Walter Cabri
Giovanni Pozzi
Paolo Ghetti
Domenico Vergani
Roberto Strigaro
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Olon SpA
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Antibioticos SpA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/36—Methylene radicals, substituted by sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

  • the present invention relates to a process for the preparation of sterile, highly crystalline sodium Cefoperazone 7-[[[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino](4-hydroxyphenyl)-acetyl]-amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, monosodium salt, [6R-[6 ⁇ ,7 ⁇ -(R*)]]), in the form of needle microcrystal agglomerates which are a further object of the invention.
  • Sodium Cefoperazone disclosed in US 4,087,424 (5/1978), is an injectable semi-synthetic cephalosporin with broad spectrum activity against resistant Gram negative bacteria, widely used in clinic due to its effectiveness in the cases of severe infections of skin, high and lower respiratory tract, central nervous system and genital-urinary system.
  • Sterile sodium Cefoperazone is available both in the amorphous (GB 1,508,071) and crystalline form (US 4,458,070, 07/1982).
  • the crystalline product, obtained by crystallization has higher purity, higher chemical stability, and lower hygroscopicity than the amorphous product, usually obtained by freeze-drying.
  • This method provides highly crystalline sodium Cefoperazone in the form of free needle microcrystals.
  • the process of the present invention comprises the salification of acid Cefoperazone in water/acetone mixtures with one equivalent of a base selected from sodium bicarbonate, sodium carbonate and sodium 2-ethylhexanoate, keeping the temperature at 5 to 25°C.
  • the sodium Cefoperazone solution is added with C 1 -C 4 aliphatic alcohols or mixtures thereof at temperatures of 20°C to 40°C.
  • Cefoperazone sodium is crystallized by addition of acetone, keeping the temperature at 20 to 40°C; said addition is preferably carried out in two portions: the first portion is sufficient to form a sodium Cefoperazone suspension, the second portion allows to complete the crystallization to a low content in sodium Cefoperazone in the mother liquors.
  • the filtration or centrifugation of the product can be carried out after 90 minutes or one day after the end of the crystallization, at the crystallization temperature (20 to 40°C) or after cooling the suspension to temperatures of 0 to 20°C.
  • the crystalline product is dried under vacuum (20 to 300 mbars) adjusting the temperature of the product to 35 - 40°C.
  • Acid Cefoperazone is salified by using preferably water/acetone/Cefoperazone ratios of 0.8-0.6/1,4-5,0/1,0 v/v/w with one equivalent of a base, preferably sodium bicarbonate, in amounts of 0.124 ⁇ 0.130 grams/ 1 gram of acid Cefoperazone, thereby obtaining water/acetone/sodium Cefoperazone solutions containing 19 ⁇ 35% of water at a temperature of 18 ⁇ 22°C.
  • the sodium Cefoperazone solution is added with alcohols or mixtures thereof selected from methanol, ethanol, n-propanol, n-butanol and isopropanol at temperatures of 20°C to 40°C, preferably at 23 to 30°C.
  • Ethanol 0.2-0.4 ml per 1 gram of acid Cefoperazone
  • isopropanol 0.2-0.8 ml per 1 gram of acid Cefoperazone
  • mixtures thereof ethanol/isopropanol: 0.2-0.4/0.2-0.8 ml per 1 gram of acid Cefoperazone
  • Sodium Cefoperazone is crystallized by adding acetone in two portions, keeping the temperature at 20 to 40°C, preferably at 23 to 30°C.
  • the first acetone portion sufficient to form a Cefoperazone sodium suspension, provides a water/acetone mixture containing 11 to 14% of water.
  • the second portion provides complete crystallization which is attained when the water/acetone mixture has water content of 3 to 5%.
  • the product may be filtered or centrifuged either 90 minutes after the end of the crystallization, at a crystallization temperature of 20 to 40°C, or after cooling the suspension to temperatures of 0 to 20°C.
  • the wet product is first washed with water/acetone mixtures containing 2 to 5% of water, and finally with pure acetone.
  • the crystalline product is dried under vacuum at 20 to 300 mbars and at 35 ⁇ 40°C.
  • the process of the invention yields crystalline sodium Cefoperazone in the form of needle microcrystals where at least 50% of the aggregates have diameter above 10 ⁇ m and at least 10% of the aggregates have diameter above 150 ⁇ m (particle size distribution was determined by laser diffraction on the dry product).
  • the crystal was washed first with a mixture of 15 ml of water and 323 ml of acetone, then with 280 ml of pure acetone. After drying for 15 hours under 1 mbar at 35°C, 36.90 grams of crystalline sodium Cefoperazone were obtained.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

Highly crystalline, highly filterable sodium Cefoperazone in the form of needle crystal aggregates, obtainable by a process comprising the controlled addition of acetone to a solution of water/acetone/alcohols/sodium Cefoperazone at 20~40° C.

Description

The present invention relates to a process for the preparation of sterile, highly crystalline sodium Cefoperazone 7-[[[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino](4-hydroxyphenyl)-acetyl]-amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, monosodium salt, [6R-[6α,7β-(R*)]]), in the form of needle microcrystal agglomerates which are a further object of the invention.
Sodium Cefoperazone, disclosed in US 4,087,424 (5/1978), is an injectable semi-synthetic cephalosporin with broad spectrum activity against resistant Gram negative bacteria, widely used in clinic due to its effectiveness in the cases of severe infections of skin, high and lower respiratory tract, central nervous system and genital-urinary system.
Sterile sodium Cefoperazone is available both in the amorphous (GB 1,508,071) and crystalline form (US 4,458,070, 07/1982). The crystalline product, obtained by crystallization, has higher purity, higher chemical stability, and lower hygroscopicity than the amorphous product, usually obtained by freeze-drying. The preparation of the product in the crystalline form is disclosed in US 4,458,070 and in US 4,456,753: US 4,458,070, (07/1982) comprises the crystallization of sodium Cefoperazone from a water/acetone/methylene chloride mixture, whereas US 4,456,753 (02/1983) discloses an improved process providing a "highly crystalline" product from the acetone/water mixture, thus avoiding the use of a toxic solvent such as methylene chloride (class 1, ICH guidelines). This method, however, provides highly crystalline sodium Cefoperazone in the form of free needle microcrystals. It is therefore difficult to filter or centrifugate the resulting suspension with the apparatuses usually employed for the preparation of sterile bulk, due to the compressibility of the product and its tendency to pack. As a consequence, drying is carried out with detriment of the process productivity and costs.
SUMMARY OF THE INVENTION
We have now surprisingly found a process for the preparation of Cefoperazone in the form of needle microcrystal agglomerates, which are easy to filter and to dry, by crystallization of the sodium salt from water/acetone mixtures in the presence of alcohols and/or mixtures thereof. The process of the present invention is therefore characterized by high productivity on the industrial scale. The resulting sodium Cefoperazone is still as highly crystalline as that disclosed in US 4,456,753.
DETAILED DISCLOSURE OF THE INVENTION
The process of the present invention comprises the salification of acid Cefoperazone in water/acetone mixtures with one equivalent of a base selected from sodium bicarbonate, sodium carbonate and sodium 2-ethylhexanoate, keeping the temperature at 5 to 25°C. The sodium Cefoperazone solution is added with C1-C4 aliphatic alcohols or mixtures thereof at temperatures of 20°C to 40°C. Cefoperazone sodium is crystallized by addition of acetone, keeping the temperature at 20 to 40°C; said addition is preferably carried out in two portions: the first portion is sufficient to form a sodium Cefoperazone suspension, the second portion allows to complete the crystallization to a low content in sodium Cefoperazone in the mother liquors. The filtration or centrifugation of the product can be carried out after 90 minutes or one day after the end of the crystallization, at the crystallization temperature (20 to 40°C) or after cooling the suspension to temperatures of 0 to 20°C. The crystalline product is dried under vacuum (20 to 300 mbars) adjusting the temperature of the product to 35 - 40°C.
Acid Cefoperazone is salified by using preferably water/acetone/Cefoperazone ratios of 0.8-0.6/1,4-5,0/1,0 v/v/w with one equivalent of a base, preferably sodium bicarbonate, in amounts of 0.124∼0.130 grams/ 1 gram of acid Cefoperazone, thereby obtaining water/acetone/sodium Cefoperazone solutions containing 19 ∼ 35% of water at a temperature of 18∼22°C. The sodium Cefoperazone solution is added with alcohols or mixtures thereof selected from methanol, ethanol, n-propanol, n-butanol and isopropanol at temperatures of 20°C to 40°C, preferably at 23 to 30°C. Ethanol (0.2-0.4 ml per 1 gram of acid Cefoperazone) or isopropanol (0.2-0.8 ml per 1 gram of acid Cefoperazone) or mixtures thereof (ethanol/isopropanol: 0.2-0.4/0.2-0.8 ml per 1 gram of acid Cefoperazone) are preferably used. Sodium Cefoperazone is crystallized by adding acetone in two portions, keeping the temperature at 20 to 40°C, preferably at 23 to 30°C. The first acetone portion, sufficient to form a Cefoperazone sodium suspension, provides a water/acetone mixture containing 11 to 14% of water. The second portion provides complete crystallization which is attained when the water/acetone mixture has water content of 3 to 5%. The product may be filtered or centrifuged either 90 minutes after the end of the crystallization, at a crystallization temperature of 20 to 40°C, or after cooling the suspension to temperatures of 0 to 20°C. The wet product is first washed with water/acetone mixtures containing 2 to 5% of water, and finally with pure acetone. The crystalline product is dried under vacuum at 20 to 300 mbars and at 35 ~ 40°C.
The process of the invention yields crystalline sodium Cefoperazone in the form of needle microcrystals where at least 50% of the aggregates have diameter above 10 µm and at least 10% of the aggregates have diameter above 150 µm (particle size distribution was determined by laser diffraction on the dry product).
DESCRIPTION OF THE FIGURE
  • Figure 1 is an optical microscope photograph of the crystalline sodium Cefoperazone in the form of needle free microcrystals obtained from acetone without using alcohols, according to US 4,456,753 (example 2).
  • Figures 2, 3 and 4 are optical microscope photographs of the crystalline sodium Cefoperazone in the form of needle microcrystal agglomerates obtained from acetone in the presence of alcohols according to the following examples 1-3, respectively.
    • EXAMPLES
    The following examples illustrate the invention in greater detail.
    Example 1 - Crystallization of sodium Cefoperazone in the presence of ethanol
    To a suspension of 39.45 grams of acid Cefoperazone in 118.8 ml of acetone at 20÷25°C, under vigorous stirring, a solution of 4.79 grams of sodium bicarbonate in 59.4 ml of purified water was added. The sodium Cefoperazone solution, pH 5.9÷6.0 at 25°C, was diluted with 8 ml of absolute ethanol without formation of precipitate. Acetone, 269 ml, was added under stirring at 25°C in 30 minutes until slight, but persistent turbidity. The suspension was stirred for 5 minutes at 25°C until intense turbidity, then 1013 ml of acetone were added dropwise in 20 minutes. After stirring for 60 minutes at 25°C, the product was recovered by filtration under vacuum. The crystal was washed first with a mixture of 15 ml of water and 323 ml of acetone, then with 280 ml of pure acetone. After drying for 15 hours under 1 mbar at 35°C, 36.90 grams of crystalline sodium Cefoperazone were obtained.
    Example 2 - Crystallization of sodium Cefoperazone in the presence of an ethanol/isopropanol mixture
    To a suspension of 39.45 grams of acid Cefoperazone in 118.8 ml of acetone at 20÷25°C, under vigorous stirring, a solution of 4.79 grams of sodium bicarbonate in 59.4 ml of purified water. The sodium Cefoperazone solution, pH 5.9÷6.0, at 25°C was diluted first with 8 ml of absolute ethanol then with 16 ml of isopropanol without formation of precipitate. Acetone, 269 ml, was added under stirring at 25°C in 25 minutes until slight, but persistent turbidity. The suspension was stirred for 5 minutes at 25°C until intense turbidity, then 1013 ml of acetone were added dropwise in 20 minutes. After stirring for 60 minutes at 25°C the product was recovered by filtration under vacuum. The crystal was washed first with a mixture of 15 ml of water and 323 ml of acetone, then with 280 ml of pure acetone. After drying for 15 hours under 1 mbar at 35°C, 37.65 grams of crystalline sodium Cefoperazone were obtained.
    Example 3 - Crystallization of sodium Cefoperazone in the presence of isopropanol
    To a suspension of 39.45 grams of acid Cefoperazone in 118.8 ml of acetone at 20÷25°C, under vigoruos stirring, a solution of 4.79 grams of sodium bicarbonate in 59.4 ml of purified water was added. The sodium Cefoperazone solution, pH 5.9÷6.0 at 25°C, was diluted with 16 ml of isopropanol without formation of precipitate. Acetone, 269 ml, was added under stirring at 25°C in 25 minutes until slight, but persistent turbidity. The suspension was stirred for 60 minutes at 25°C until intense turbidity, then 1013 ml of acetone were added dropwise in 20 minutes. After stirring for 60 minutes at 25°C the product was recovered by filtration under vacuum. The crystal was washed first with a mixture of 15 ml of water and 323 ml of acetone, then with 280 ml of pure acetone. After drying for 15 hours under 1 mbar at 35°C, 37.52 grams of crystalline sodium Cefoperazone were obtained.

    Claims (6)

    1. A process for the preparation of crystalline sodium Cefoperazone in the form of needle microcrystal aggregates, which comprises the following steps:
      a) preparation of a water/acetone/sodium Cefoperazone solution containing 19 ∼ 35% of water;
      b) addition of a C1-C4 aliphatic alcohol or a mixture thereof;
      c) crystallisation by the addition of acetone.
    2. A process according to claim 1 wherein the aliphatic alcohol is selected from ethanol, isopropanol or mixtures of ethanol and isopropanol.
    3. A process according to claims 1 or 2 wherein acetone is added in two portions.
    4. A process according to claim 3 wherein a first acetone portion is added to obtain a suspension containing from 11 to 14% of water and a second acetone portion is added to obtain a suspension containing from 3 to 5% of water.
    5. Aggregates of crystalline sodium Cefoperazone in the form of needle microcrystals aggregates obtainable by the process of any one of claims 1-4.
    6. Aggregates of crystalline sodium Cefoperazone as claimed in claim 5, where at least 50% of the aggregates have diameter above 10 µm and at least 10% of the aggregates have a diameter above 150 µm.
    EP01940312A 2000-04-14 2001-04-10 A process for the preparation of highly crystalline sodium cefoperazone Expired - Lifetime EP1272495B1 (en)

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    ITMI000837 2000-04-14
    IT2000MI000837A IT1318467B1 (en) 2000-04-14 2000-04-14 HIGHLY CRYSTALLINITY SODE CEFOPERAZONE SYNTHESIS PROCESS.
    PCT/EP2001/004074 WO2001079210A2 (en) 2000-04-14 2001-04-10 A process for the preparation of highly crystalline sodium cefoperazone

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    EP1272495B1 true EP1272495B1 (en) 2004-06-30

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    EP (1) EP1272495B1 (en)
    JP (1) JP2003531147A (en)
    KR (1) KR20030005281A (en)
    AT (1) ATE270296T1 (en)
    AU (1) AU2001273933A1 (en)
    DE (1) DE60104103T2 (en)
    DK (1) DK1272495T3 (en)
    ES (1) ES2223871T3 (en)
    IT (1) IT1318467B1 (en)
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    TR (1) TR200401624T4 (en)
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    US20040092735A1 (en) * 2002-11-08 2004-05-13 Orchid Chemicals & Pharmaceuticals Limited Process for the preparation of cefuroxime sodium
    KR100608056B1 (en) 2004-06-05 2006-08-02 삼성전자주식회사 Apparatus for reproducing a multimedia content, a reproducing method, a generating device, a generating method, and a storage medium storing the multimedia content
    CN101863907B (en) * 2010-07-07 2012-05-23 福建省福抗药业股份有限公司 Method for crystallizing cefoperazone sodium
    WO2014012849A1 (en) * 2012-07-17 2014-01-23 Dsm Sinochem Pharmaceuticals Netherlands B.V. A new crystal form of cefoperazone sodium
    CN103951679B (en) * 2014-04-29 2016-04-27 悦康药业集团有限公司 A kind of cefoperazone sodium compound and pharmaceutical composition thereof
    CN104327099A (en) * 2014-09-29 2015-02-04 联合康兴（北京）医药科技有限公司 Cefoperazone sodium compound entity, composition and application
    CN112279868B (en) * 2020-09-24 2021-10-15 华北制药河北华民药业有限责任公司 Method for purifying cefoperazone sodium
    CN116143803B (en) * 2023-01-29 2024-11-08 山东省分析测试中心 Preparation method of large-particle cefoperazone sodium spherical crystals

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    * Cited by examiner, † Cited by third party
    Publication number Priority date Publication date Assignee Title
    GB1508071A (en) * 1976-01-19 1978-04-19 Toyama Chemical Co Ltd Cephalosporins and process for producing the same
    US4456753A (en) * 1983-02-07 1984-06-26 Pfizer Inc. Process for the manufacture of highly crystalline sodium cefoperazone

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    ITMI20000837A0 (en) 2000-04-14
    IT1318467B1 (en) 2003-08-25
    WO2001079210A2 (en) 2001-10-25
    ATE270296T1 (en) 2004-07-15
    DK1272495T3 (en) 2004-11-22
    TR200401624T4 (en) 2004-08-23
    ES2223871T3 (en) 2005-03-01
    DE60104103T2 (en) 2004-11-11
    EP1272495A2 (en) 2003-01-08
    ITMI20000837A1 (en) 2001-10-14
    JP2003531147A (en) 2003-10-21
    AU2001273933A1 (en) 2001-10-30
    WO2001079210A3 (en) 2002-02-21
    DE60104103D1 (en) 2004-08-05
    KR20030005281A (en) 2003-01-17
    PT1272495E (en) 2004-09-30
    US20040030127A1 (en) 2004-02-12

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